This is the second edition of this guideline which was first published in 2007 under the same title.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 Green-top Guideline No. 48 Peer Review Draft September 2015 Management of Premenstrual Syndrome This is the second edition of this guideline which was first published in 2007 under the same title. 1. Purpose and scope The aim of this guideline is to review the diagnosis, classification and management of premenstrual syndrome (PMS). The evidence for pharmacological and nonpharmacological treatments is examined. 2. Introduction and background epidemiology Since the 2007 guideline, there has been considerable work by the International Society for Premenstrual Disorders (ISPMD) and the National Association for Premenstrual Syndrome (NAPS) to achieve consensus on the recognition, diagnosis, classification and management of PMS. Misdiagnosis of PMS (e.g. confusion with bipolar disorder) and the use of a wide range of treatments, often with little evidence for effectiveness and safety, demand that these issues are addressed. 2.1 Definition of PMS PMS encompasses a vast array of psychological and physical symptoms; depression, anxiety, irritability, loss of confidence, mood swings and physical symptoms such as bloatedness and mastalgia are typical. It is the timing, rather than the type of symptom, and the degree of impact on daily activity that supports a diagnosis of PMS. The character of symptoms in an individual patient does not influence the diagnosis. In order to differentiate physiological menstrual symptoms from PMS, it must be demonstrated that symptoms cause significant impairment to the individual during the luteal phase of the menstrual cycle. 1 2.2 Classification of PMS (ISPMD consensus) Core premenstrual disorders (core PMD) are the most commonly encountered and widely recognised type of PMS. As with all premenstrual disorders, symptoms must be severe enough to affect daily functioning or interfere with work, school performance or interpersonal relationships. The symptoms of core PMD are nonspecific and recur in ovulatory cycles. They must be present during the luteal phase and abate as menstruation begins, which is then followed by a symptom-free week. There is no limit on the type or number of symptoms experienced; however, some individuals will have predominantly psychological, predominantly somatic or a mixture of symptoms. There are also PMDs that do not meet the criteria for core PMDs. These are called variant PMDs and fall into four subtypes. 1. Premenstrual exacerbation of an underlying disorder, such as diabetes, depression, epilepsy, asthma and migraine. These patients will experience symptoms relevant to their disorder throughout the menstrual cycle. 2. Non-ovulatory premenstrual disorders occur in the presence of ovarian activity without ovulation. This is poorly understood due to a lack of evidence, but it is thought that follicular activity of the ovary can instigate symptoms. Page 1 of 25

52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 3. Progestogen-induced premenstrual disorders are caused by exogenous progestogens present in hormone replacement therapy (HRT) and the combined oral contraceptive pill. This reintroduces symptoms to women who may be particularly sensitive to progestogens. Although progestogenonly contraceptives may introduce symptoms, as they are noncyclical they are not included within variant PMDs and are considered adverse effects (probably with similar mechanisms) of continuous progestogen therapy. 4. Premenstrual disorders without menstruation include women who still have a functioning ovarian cycle, but for reasons such as hysterectomy, endometrial ablation or the levonorgestrelreleasing intrauterine system (LNG-IUS) they do not menstruate. 2 Care must be taken not to label women with underlying psychiatric or somatic disorders that do not appear to be influenced by the menstrual cycle as having PMS. 2.3 Prevalence and aetiology Four in ten women (40%) experience symptoms of PMS and, of these, 5 8% suffer from severe PMS. 3 A cross-sectional survey of 974 women based in Southampton revealed a 24% prevalence of premenstrual symptoms after completing a 6-week prospective symptom diary. 4 Although the aetiology remains uncertain, it revolves around the ovarian hormone cycle, which is reinforced by the absence of PMS prior to puberty, during pregnancy and after the menopause. Currently two theories predominate and appear interlinked. The first suggests that some women are sensitive to progesterone and progestogens, since the serum concentrations of estrogen or progesterone are the same in those with or without PMS. The second theory implicates the neurotransmitters serotonin and γ-aminobutyric acid (GABA). Serotonin receptors are responsive to estrogen and progesterone and selective serotonin reuptake inhibitors (SSRIs) are proven to reduce PMS symptoms. GABA levels are modulated by the metabolite of progesterone, allopregnanolone, and in women with PMS, the allopregnanolone levels appear to be reduced. 5 3. Identification and assessment of evidence This guideline was developed in accordance with standard methodology for producing RCOG Greentop Guidelines. The Cochrane Library (including the Cochrane Database of Systematic Reviews and DARE), EMBASE, Trip, MEDLINE (1966 2013), Psych INFO (1960 2013), CINAHL (1982 2013) and the British Nursing Index (BNI) (1985 2013) were searched. The databases were searched using the relevant Medical Subject Headings (MeSH) terms, including all subheadings, and this was combined with a keyword search. Search words included premenstrual syndrome, premenstrual tension, late luteal phase dysphoric disorder, premenstrual dysphoric disorder, PMDD, PMS, PMD, LLPDD, PMT and the search was limited to humans and the English language. 4. How is PMS diagnosed? When clinically reviewing women for PMS, symptoms should be recorded prospectively, over two cycles using a symptom diary, as retrospective recall of symptoms is unreliable. [GPP] A symptom diary should be completed by the patient prior to commencing treatment. [GPP] Gonadotrophin-releasing hormone (GnRH) analogues may be used for 3 months for a definitive diagnosis if the completed symptom diary alone is inconclusive. [GPP] There are many patient-rated questionnaires available. However, the Daily Record of Severity of Problems (DRSP) remains the most widely used and is simple for patients to use. 2 The DRSP has also Page 2 of 25

103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 been consistently shown to provide a reliable and reproducible record of symptoms (see Appendix I). 6 The Premenstrual Symptoms Screening Tool (PSST) is another patient-rated questionnaire; however, it is retrospective and has not been validated. Various attempts at electronic data capture have been attempted. Commercially available diagnostic apps, such as PreMentricS, are now available, but these too require validation. Another easily accessible symptom diary exists on the NAPS website (www.pms.org.uk). This diary is not validated but is sufficient to be used in the context of clinical practice. 7 Symptom diaries should be completed before any form of treatment over at least two consecutive menstrual cycles. Treatment may improve symptoms, therefore masking underlying PMS, but it can also create a pattern of symptoms incompatible with a diagnosis of PMS, making the interpretation of DRSP charts confusing. These charts should be brought with the patient to any future appointments. Symptom diaries can sometimes be confusing and inconclusive: for example, when a form of treatment has already been commenced. This is most likely to occur in those patients with variant PMD. GnRH analogues, which are widely used within gynaecology, can be useful in separating those with and those without PMS by inhibiting cyclical ovarian function. These should be used for 3 months to establish a definitive diagnosis. This is to allow a month for the agonist to generate a complete hormonal suppressive effect, as well as providing 2 months worth of symptom diaries. 5. What aspects are involved in delivering a service to women with PMS? 5.1 When should women with PMS be referred to a gynaecologist? Referral to a gynaecologist should be considered when simple measures have been explored and failed and when the severity of the PMS justifies gynaecological intervention. [GPP] General practitioners will manage the majority of cases of PMS; therefore, awareness of the condition together with up-to-date information on its management is essential. Referral to secondary care should be reserved for those with confirmed PMS in whom simple measures have failed to control symptoms. In women whose symptom diaries demonstrate noncyclical psychological symptoms, an underlying psychiatric or somatic disorder should be considered. 5.2 Who are the key health professionals to manage women with severe PMS? Women with severe PMS may benefit from being managed by a multidisciplinary team comprising a general practitioner, a general gynaecologist or a gynaecologist with a special interest in PMS, a mental health professional (psychiatrist, clinical psychologist or counsellor) and a dietician. [GPP] While this set-up is desirable, it is certainly not widely available or implemented within the National Health Service (NHS) due to financial and organisational challenges. There are specialist clinics within tertiary centres to which patients can be referred. However, it is likely that the general practitioner will remain key in facilitating potential treatments. The multidisciplinary team can offer women an individualised management plan utilising a range of treatments, such as cognitive behavioural therapy (CBT) and lifestyle interventions, to manage their symptoms. 8 6. How is PMS managed? 6.1 Are complementary therapies efficacious in treating PMS? Page 3 of 25

154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 Women with PMS should be informed that there is conflicting evidence to support the use of complementary medicines. [C] An integrated holistic approach should be used when treating women with PMS. [GPP] Interactions with conventional medicines should be considered. [GPP] Although there is limited evidence to support the use of complementary therapies, it is agreed among health professionals treating women with PMS that a holistic approach is beneficial for the majority of women. 9 This is particularly important for women in whom hormonal therapy is contraindicated. In the UK, the most efficacious treatments are unlicensed. Evidence level 1 Table 1 summarises current research into the benefits of selected complementary therapies for the treatment of PMS. Dante et al. 10 conducted a systematic review into herbal remedies for PMS. Four of the trials, including 500 women, supported the use of Vitex agnus-castus (a herb known as chasteberry). However, the study concluded that there were inadequate safety data to support its use. Whelan et al. 11 conducted a systematic review of 29 randomised controlled trials (RCTs). Two of these studies (n = 499) revealed consistent evidence for calcium in alleviating both physical and psychological symptoms of PMS. The evidence for vitamin B6 and Vitex agnus-castus was discordant. Due to the lack of power, reliable recommendations cannot be provided. A systematic review 12 focusing on the use of Vitex agnus-castus illustrated in seven out of eight RCTs that Vitex agnus-castus was superior to placebo in the treatment of PMS. In one study, it appeared comparable to fluoxetine. The safety of Vitex agnus-castus is described as excellent, with adverse effects being infrequent and mild. However, SSRI drugs should not be used concurrently with St John's wort. Evidence level 1 Page 4 of 25

183 184 Table 1. Summary of evidence for selected complementary therapies Complementary Benefit Types of studies Numbers in the study Note therapy Exercise 13 16 Some benefit Nonrandomised and randomised 72 (4 published studies) High quality studies recommended Reflexology 17 Some benefit Randomised 35 Vitamin B6 18 30 Mixed results Double-blind Randomised Cross-over Magnesium 28,31,32 Mixed results Double-blind Randomised Cross-over Multivitamins 33 36 Unknown 400 (several published studies) Calcium/vitamin D 37,38 Yes Double-blind Randomised Cross-over Isoflavones 39,40 Mixed results Double-blind Randomised Cross-over Vitex agnus-castus 30,41 43 Yes Double-blind randomised St John s wort 44 No Double-blind Placebo-controlled 1067 (13 published studies) Peripheral neuropathy with high doses (most studies performed using higher doses). Department of Health and Maternal and Child Health restrict the daily dose to 10 mg. 153 (3 published studies) Used in premenstrual phase 499 (2 published studies) Unclear which are the active ingredients 72 (2 published studies) May benefit menstrual migraine. 560 (4 published studies) There is no standardised preparation 125 Many withdrew from the study due to adverse effects. Significant interactions with conventional medicines. The British National Formulary (BNF) advises avoid concomitant use with SSRIs. Ginkgo biloba 45 Some benefit Double-blind Placebo-controlled 143 Pollen extract 46 Yes Double-blind 47 Further data before recommendation Placebo-controlled Evening primrose oil 47 49 No Double-blind 95 (3 published studies) May benefit women with cyclical breast symptoms Placebo-controlled Cross-over Acupuncture 50 58 Some benefit Case control 545 (9 published studies) Further data before recommendation Page 5 of 25

185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 6.2 Is there a role for cognitive behavioural therapy (CBT) and other psychological counselling techniques? When treating women with severe PMS, CBT should be considered routinely as a treatment option. [A] Hunter et al. 59 conducted a randomised trial comparing fluoxetine, CBT and the combination of fluoxetine and CBT for the treatment of premenstrual dysphoric disorder (PMDD). After a 6-month treatment period, all three treatment groups showed evidence of benefit and this was similar between the groups, with fluoxetine combined with CBT no more effective than the two component therapies used separately. Fluoxetine showed quicker improvements, but the effects of CBT were thought to be longer lasting. Evidence level 1+ A meta-analysis identified five RCTs testing CBT against a control intervention. The evidence was poor but demonstrated a significant reduction in depression, anxiety and behavioural problems. If CBT proves successful to a patient it would avoid pharmacotherapy and potential adverse effects. 60 Evidence level 1 6.3 Medical management of PMS 6.3.1 What is the role of cycle-modifying agents in managing PMS (including the combined contraceptive pill)? 6.3.1.1 Which combined oral contraceptive has the best evidence for managing PMS, including regimens delivering ethinylestradiol? When treating women with PMS, drospirenone-containing combined oral contraceptives may represent effective treatment for PMS and should be considered as a first-line pharmaceutical intervention. [B] Despite the combined pill s ability to suppress ovulation, studies initially illustrated no benefit in the treatment of PMS. 61 This may be attributed to the progestogens in second-generation pills (levonorgestrel or norethisterone) regenerating PMS-type symptoms. Further research has therefore been directed towards new combined contraceptives, in particular those containing the antimineralocorticoid and anti-androgenic progestogen, drospirenone. Evidence level 2+ A Cochrane review 62 involving five RCTs and 1920 participants looked into the effectiveness of drospirenone (3 mg) and ethinylestradiol combined oral contraceptives against placebo and an alternative combined oral contraceptive, where the progestogen was substituted for desogestrel (150 micrograms) or levonorgestrel (150 micrograms). This concluded that, when compared with placebo, drospirenone-containing oral contraceptives used for 3 months did reduce the severity of symptomatology in PMDD sufferers (mean difference 7.92; 95% CI 11.16 to 4.67). The severity of symptoms was rated using validated questionnaires and where nonvalidated tools were used the original data were analysed. Evidence level 1 A double-blind, placebo-controlled cross-over trial of 450 subjects showed drospirenone 3 mg and ethinylestradiol 20 micrograms to be effective for treating PMDD, based upon DRSP chart scoring. The mean decrease from baseline scoring was 12.47 (95% CI 18.28 to 6.66, P < 0.001). Participants were allocated to their initial treatment arm for three cycles and swapped to the alternative treatment arm after one cycle treatment-free. This oral contraceptive is not available on Page 6 of 25

236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 the NHS in the UK but is licensed in Europe and the USA for PMDD in women requiring oral contraception. 63 Evidence level 1+ Another double-blind RCT of 450 participants comparing the same contraceptive pill with placebo also supported its use in PMDD. 64 Evidence level 1+ 6.3.1.2 What is the optimum combined oral contraceptive pill regimen e.g. continuous, cyclical or flexible? When treating women with PMS, emerging data suggest use of the contraceptive pill continuously rather than cyclically. [GPP] Continuous therapy would seem appropriate; there are some data to support this. Phase I of a study showed that a 168-day extended regimen of drospirenone and ethinylestradiol led to a significant decrease in premenstrual-type symptoms compared with a standard 21/7-day regimen. 65 Phase II of this trial extended the continuous use of this combined oral contraceptive for a total of 364 days. Menstrual symptoms were recorded using DRSP charts. The results concluded that mood, headache and pelvic pain scores improved when compared with a 21/7-day regimen. There was a high level of satisfaction, with most women continuing on this regimen 6 months on from the 364-day trial. 66 This trial used a preparation currently available in the UK as a 21/7-day regimen containing 30 micrograms ethinylestradiol and 3 mg drospirenone; however, phase II of the study supports continuous use and this may be considered. Evidence level 2 6.3.2 How efficacious is percutaneous estradiol with progesterone/progestogens/lng-ius as progestogenic opposition? Percutaneous estradiol combined with cyclical progestogens has been shown to be effective for the management of physical and psychological symptoms of severe PMS. [A] When treating women with PMS, alternative barrier or intrauterine methods of contraception should be used when estradiol is used to suppress ovulation. [GPP] Percutaneous preparations give sufficient estradiol levels to suppress ovarian activity. A placebocontrolled trial demonstrated that implants of 17β-estradiol combined with cyclical progestogens are effective for the management of severe PMS symptoms. Administered as a 100-mg implant, this proved to be highly effective when compared with placebo. 67 Both implants and patches have been evaluated in controlled trials but gels have not. Evidence level 1+ In a randomised, double-blind, placebo-controlled trial of 20 women with cross-over at 3 months, transdermal estradiol patches (200 micrograms) were assessed and found to be highly effective. 68 Significant improvements occurred after changing to active treatment, proven by the use of symptom questionnaires. There was concern that estradiol 200 micrograms twice weekly was still too high a dose to be used as long-term therapy. A subsequent randomised study 69 showed that 100-microgram estradiol patches twice weekly were as effective as 200 micrograms in reducing symptom levels in severe PMS and this dosage was better tolerated. 70 These findings have been backed up by a Cochrane review, which showed equal efficacy between implants and patches. 71 Evidence level 1+ Although doses are usually sufficient to suppress ovulation, contraceptive efficacy has not been demonstrated and so should not be relied upon; additional contraceptive measures should be adopted. Page 7 of 25

287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 6.3.3 How can the return of PMS symptoms be avoided during estrogen therapy with progestogenic protection? When using transdermal estrogen to treat women with PMS, the lowest possible dose of progesterone or progestogen is recommended to minimise progestogenic adverse effects. [A] Women should be informed that low levels of levonorgestrel released by the LNG-IUS can initially produce PMS-type adverse effects (as well as bleeding problems). [GPP] Natural progesterone is theoretically less likely to reintroduce PMS-like symptoms and should therefore be considered as first line for progestogenic opposition rather than progestogens. [GPP] Use of continuous estradiol necessitates the addition of cyclical progesterone or progestogens (10 12 days) to avoid endometrial hyperplasia in women who have a uterus. A study of long-term treatment with the 100 mg dosage using a low dose of cyclical norethisterone acetate (NETA; 1 mg; 10 days/cycle) has shown benefit over placebo over eight cycles, with continued improvement in a 6-month extension. 72 Evidence level 1+ Intrauterine administration of progestogen has the potential to avoid systemic absorption and hence avoid progestogenic effects. The LNG-IUS as progestogen replacement can maximise efficacy by minimising PMS-like adverse effects. Low systemic levels of levonorgestrel released by the LNG-IUS can initially produce PMS-type adverse effects (as well as bleeding) in the progestogen-intolerant woman and on rare occasions it will need to be removed due to persistent PMS-type adverse effects. It might still be of advantage to use a LNG-IUS or vaginal progesterone (pessaries, 100 200 mg vaginal capsules, or 8% gel untested and not licensed for this indication in this age group) in the progestogen-intolerant woman. 73 75 Micronised oral progesterone has fewer androgenic and unwanted adverse effects compared with progestogens such as norethisterone and levonorgestrel. Progesterone is a natural diuretic and a central nervous system anxiolytic and so in theory could also alleviate PMS symptoms, although there is currently little evidence to demonstrate this. 73 Micronised progesterone (100 mg/200 mg orally) can also be administered vaginally, which may be better tolerated by avoiding first-pass hepatic metabolism. Vaginally administered progesterone avoids the formation of psychoactive metabolites such as allopregnanolone. Evidence level 4 6.3.4 What is the optimum regimen for prevention of endometrial hyperplasia? When treating women with percutaneous estradiol, a cyclical 10 12 day course of oral or vaginal progesterone or long-term progestogen with the LNG-IUS should be used for the prevention of endometrial hyperplasia. [GPP] When using a short duration of progestogen therapy, or in cases where only low doses are tolerated, there should be a low threshold for investigating unscheduled bleeding. [GPP] The lowest dose for the shortest time should reduce unwanted progestogenic effects and therefore an oral dose (micronised progesterone 100 mg or norethisterone 2.5 mg) for the first 10 12 days of each calendar month should be sufficient. 70 Evidence level 4 6.3.5 What is the safety of estradiol on the premenopausal endometrium and breast tissue? Page 8 of 25

338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 When treating women with PMS using estradiol, women should be informed that there are insufficient data to advise on the long-term effects on breast and endometrial tissue. [GPP] There is insufficient evidence to determine whether there is an increased risk of endometrial or breast carcinoma in premenopausal women using percutaneous patches and cyclical progestogens or the LNG-IUS. Randomised placebo-controlled trial data in large populations looking at major outcome measures over a long period of time are lacking. 6.3.6 For how long can estradiol be used safely and what is the risk of recurrence? Due to the uncertainty of the long-term effects of opposed estradiol therapy, treatment of women with PMS should be on an individual basis, taking into account the risks and benefits. [GPP] Treatment of PMS is required as long as the woman s ovarian cycle continues to function. Discontinuation of treatment could trigger a return of premenstrual symptoms. A reliable long-term treatment is therefore essential. This should be seriously considered when evaluating treatment options. Unlike premature ovarian failure, women with PMS still have a functioning endogenous hormone cycle. With this in mind, there are no long-term data among this specific cohort of patients. 6.3.7 What is the evidence for efficacy and adverse effects of danazol in the treatment of PMS? Women with PMS should be advised that, although treatment with low-dose danazol (200 mg twice daily) is effective, it also has potential irreversible virilising effects. [A] Women treated with danazol for PMS should be advised to use contraception during treatment. [GPP] Cycle suppression may be achieved using danazol, an androgenic steroid. Mansel et al. first assessed the effect of danazol on PMS symptoms in a study randomised on the basis of the complaint of breast tenderness. 76 It demonstrated benefit for breast but not other PMS symptoms. Other studies have shown greater benefit. 77,78 A randomised, double-blind, cross-over study compared three successive cycles of danazol at a dose of 200 mg twice daily with three cycles of placebo. 78 Twentyeight of 31 women completed at least one cycle of treatment while recording symptoms. From this study, the authors demonstrated that danazol at a dose of 200 mg twice daily was superior to placebo for the relief of severe PMS during the premenstrual period. However, this superiority is muted or even reversed when the entire cycle is considered. This may be explained by the fact that danazol therapy does have some adverse effects, which may interfere with the usual symptom-free late follicular phase of women with PMS. One solution suggested for this problem might be to limit danazol treatment to the luteal phase only. One study of danazol given in the luteal phase demonstrated improvement in breast symptoms only, but with minimal adverse effects. 79 Evidence level 1+ 6.3.8 How effective are GnRH analogues for treating severe PMS? When treating women with PMS, GnRH analogues should usually be reserved for women with the most severe symptoms and not recommended routinely unless they are being used to aid diagnosis or treat particularly severe cases. [GPP] Page 9 of 25

388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 GnRH analogues suppress ovarian steroid production and therefore cause a drastic improvement or complete cessation of symptoms in patients with core PMD. A meta-analysis identified 71 women on active treatment in seven trials. The overall standardised mean difference (SMD) for all trials was 1.19 (95% CI 1.88 to 0.51; Cohen criteria: 0.3 small, 0.5 medium, 1.0 large effect). The OR for benefit was 8.66 (95% CI 2.52 30.26). The SMD was 1.43 and OR 13.38 (95% CI 3.9 46.0) if data were taken only from anovulation trials. Efficacy of symptom relief was greater for physical than for behavioural symptoms (physical SMD 1.16, 95% CI 1.53 to 0.79; behavioural SMD 0.68, 95% CI 1.11 to 0.25) but the difference was not significant (P = 0.484). If GnRH analogue therapy does not result in elimination of premenstrual symptoms, a lack of efficacy suggests a questionable diagnosis rather than a limitation of therapy. 80 Evidence level 1++ 6.3.9 How should women with PMS receiving add-back therapy be managed? When treating women with severe PMS using GnRH analogues for more than 6 months, add-back hormone therapy should be used. [A] When add-back hormone therapy is required, continuous combined HRT or tibolone is required. [A] Women should be provided with general advice regarding the effects of exercise, diet and smoking on bone mineral density. [GPP] Women on long-term treatment should have annual measurement of bone mineral density (ideally by dual-energy X-ray absorptiometry [DEXA]). Treatment should be stopped if bone density declines significantly. [D] As symptoms return with the onset of ovarian function, therapy may (rarely) have to be continued indefinitely; GnRH alone is precluded by significant trabecular bone loss which can occur with only 6 months of treatment. It should be noted that GnRH analogues are only licensed for use for 6 months when used alone and are not licensed to treat PMS. 81 Evidence level 1++ Continuous combined therapy or tibolone is preferable to sequential combined therapy in order to minimise the risks of symptom reappearance of PMS-like progestogenic effects. 82,83 Both of these methods of add-back HRT combat the hypoestrogenic symptoms apparent with GnRH analogues but also maintain bone mineral density. The overall SMD favoured neither GnRH alone nor GnRH with add-back (SMD 0.12, 95% CI 0.34 to 0.59), demonstrating there is no reversal of the beneficial effect of GnRH when using add-back. 80 Evidence level 1++ DEXA is accepted as the gold standard investigation for assessing bone mineral density. 84 Annual DEXA scans are considered useful as less frequent scans would delay diagnosis of significant bone loss and subsequent review of GnRH analogue treatment and more frequent scans may not perceive small changes. Evidence level 4 6.3.10 Can GnRH analogues be useful in clarification of diagnostic category? When the diagnosis of PMS is unclear from 2 months prospective DRSP charting, GnRH analogues can be used to establish and/or support a diagnosis of PMS. [GPP] Although not licensed for this indication, GnRH analogues are widely used as a diagnostic tool. There is currently no evidence to support their use in PMS diagnostically, but extrapolating from the evidence available for treatment of PMS with GnRH analogues, it seems a logical option. Page 10 of 25

439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 6.3.11 What is the role for progesterone and progestogen preparations in treating PMS? There is insufficient evidence to recommend the routine use of progesterone or progestogens for women with PMS. [A] Continuous progestogen therapy may introduce PMS-like symptoms in a continuous fashion and is unlikely to lead to improvement in women with PMS. It is therefore not recommended in the treatment of severe PMS. [GPP] There is no evidence to support the use of the LNG-IUS to treat PMS symptoms. Its role should be confined to opposing the action of estrogen therapy on the endometrium. [GPP] A meta-analysis of all published studies for progestogen and progesterone treatment of PMS demonstrated no benefit for treatment. 85 The objective of this systematic review was to evaluate the efficacy of progesterone and progestogens in the management of PMS. Ten trials of progesterone therapy (531 women) and four trials of progestogen therapy (378 women) were reviewed. The main outcome measure was a reduction in overall symptoms of PMS. All the trials of progesterone (by both routes of administration) showed no clinically significant difference between progesterone and placebo. For progestogens, the overall SMD for reduction in symptoms showed a slight nonsignificant difference in favour of progestogen, with the mean difference being 0.036 (95% CI 0.059 to 0.014). Evidence level 1++ A Cochrane review has also shown that the evidence for or against the use of progesterone or progestogens in PMS is equivocal. Seventeen studies were identified but only two were eligible; however, they could not be combined in a meta-analysis due to differences in study design, participants and progesterone dose. 86 Overall, these studies were of poor quality. Evidence level 1 There is no evidence to support the use of the LNG-IUS to treat PMS symptoms. Some women with PMS are particularly sensitive to even minute doses of progestogen and therefore the LNG-IUS may prolong PMS symptomatology. The intrauterine device s main function in PMS management is to oppose the action of estrogen therapy on the endometrium, ideally without provoking systemic symptoms. Evidence level 4 6.4 How do selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs) work in PMS and how should they be given? 6.4.1 What is the efficacy of SSRIs in treatment of PMS? SSRIs/SNRIs should be considered one of the first-line pharmaceutical management options in severe PMS. [A] When treating women with PMS, either luteal or continuous dosing with SSRIs can be recommended. [B] Women with PMS have been shown to have low concentrations of serotonin within their platelets and this varies throughout the menstrual cycle. 87 Evidence level 2+ The exact mode of action of SSRIs is unknown in PMS; however, both estrogen and progesterone have the ability to regulate the number of serotonin receptors in rat studies and human positron emission tomography (PET) studies. 88 90 Page 11 of 25

490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 A Cochrane review analysed data from 31 RCTs comparing SSRIs with placebo. SSRIs compared included fluoxetine, paroxetine, sertraline, escitalopram and citalopram. Nine studies involving 1276 women with PMS used a moderate dose SSRI and this showed that symptoms improved when compared with placebo (SMD 0.65, 95% CI 0.46 to 0.84). 91 There are also data supporting the use of SNRIs for PMDD. 92 Evidence level 1 When comparing continuous dosing versus luteal dosing there was no significant difference between these regimens. SSRIs appear to be effective for both physical and psychological symptoms. 91 Evidence level 1 A meta-analysis looked at 29 double-blind RCTs including 2964 women with PMS. This concluded that SSRIs are effective in treating PMS (OR 0.40, 95% CI 0.31 0.51); however, intermittent dosing appeared less favourable than continuous dosing (OR 0.55, 95% CI 0.45 0.68 and OR 0.28, 95% CI 0.18 0.42 respectively). No particular SSRI appeared to be better than another. 93 Evidence level 1+ 6.4.2 Is there any evidence on how SSRIs should be discontinued when used in PMS? SSRIs should be discontinued gradually to avoid withdrawal symptoms, if given on a continuous basis. [GPP] Gastrointestinal disturbances, headache, anxiety, dizziness, paraesthesia, sleep disturbances, fatigue, influenza-like symptoms and sweating are the most common features of abrupt withdrawal of an SSRI or marked reduction of the dose; the dose should be tapered over a few weeks to avoid these effects. 6.4.3 Do the benefits outweigh the risks and adverse effects? Women with PMS treated with SSRIs should be warned of the possible adverse effects such as nausea, insomnia, fatigue and reduction in libido. [GPP] In the Cochrane review, women with PMS were more likely to discontinue treatment due to adverse effects when compared with placebo (OR 2.55, 95% CI 1.84 3.53). The most common symptoms were nausea, asthenia, somnolence, fatigue, decreased libido and sweating. All of these adverse effects are dose-dependent. 93 Evidence level 1+ The Commission on Human Medicines endorses the view that SSRIs are effective medicines in the treatment of depression and anxiety conditions and that the balance of risks and benefits in adults remains positive in their licensed indications. 94 6.4.4 Is there evidence for improved efficacy with other SSRI/SNRI regimens? When using SSRIs/SNRIs to treat PMS, efficacy may be improved and adverse effects minimised by the use of luteal-phase regimens with the newer agents. [A] The use of newer SSRIs, such as citalopram, may produce resolution of symptoms where other SSRIs have failed. 95 Severe PMS also improves significantly with either luteal-phase or symptom-onset dosing of escitalopram with good tolerability. 96 Women with more severe PMS may respond better to luteal-phase dosing than symptom-onset dosing. There are also data supporting the use of SNRIs for PMDD. 92 Evidence level 1+ Page 12 of 25

541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 More recently, efforts have been made to evaluate the efficacy of other psychotropic medications that may cause fewer adverse effects. An example of this is a single-blinded RCT comparing the efficacy of buspirone 10 mg (an anxiolytic medication) versus fluoxetine 20 mg in controlling PMS symptoms. Seventy-five women were confirmed to have PMS using the Diagnostic and Statistical Manual of Mental Disorders (fourth edition; DSM-IV) criteria and allocated to either buspirone or fluoxetine for 2 months. Participants were assessed by the use of a questionnaire pretreatment, at 1 month and after 2 months of the allocated treatment. The questionnaire involved 15 categories of both physical and psychological symptoms including a 4-point rating scale. Results revealed a statistically significant improvement in symptom rating at both 1 month and 2 months in both treatment arms (fluoxetine baseline score 19.5, 1 month 15.07, 2 months 10.65, P < 0.001; buspirone baseline score 17.35, 1 month 13.91, 2 months 8.86, P < 0.001). There was no difference between treatment groups. 97 Evidence level 1 6.4.5 What preconception and early pregnancy advice should be given regarding SSRIs? Women should be provided with prepregnancy counselling at every opportunity. They should be informed that PMS symptoms will improve during pregnancy and therefore SSRIs should be discontinued prior to and during pregnancy. [B] Women who take SSRIs in early pregnancy are at a small increased of fetal congenital malformations, particularly cardiac septal defects. However, there is currently uncertainty about the relative safety of one SSRI/SNRI over another. 98 The potential risk of septal defects is of greater relevance to women with PMS as the heart is largely formed by 5 weeks of gestation (i.e. before most women with PMS discover that they are pregnant). A population-based cohort study looked at 493 113 children born in Denmark and the major congenital malformation risk in those exposed in utero to SSRIs. They found that SSRIs were not associated with major congenital malformations overall but did appear to be associated with septal defects. The risk was slightly higher (0.9%) in those taking one SSRI when compared with those taking no SSRIs (0.5%). This risk increased further in those taking two SSRIs (2.1%). However, it remains unclear if this increased risk was a direct effect of medication as opposed to environmental factors and/or the underlying psychiatric disorder. 99 SSRI use after 20 weeks of gestation is also associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN). 100 Further research is being directed towards the risk of smallfor-gestational-age babies, preterm birth and neurological problems, such as autism. 101 As of yet, there is no evidence to implicate SSRIs in the development of these problems and as pregnancy abolishes symptoms of PMS, women are unlikely to require treatment throughout pregnancy. Evidence level 2+ 6.5 How can PMS be managed surgically? 6.5.1 Can surgical management of PMS be justified and is it efficacious? When treating women with severe PMS, hysterectomy and bilateral salpingo-oophorectomy has been shown to be of benefit. [C] When treating women with PMS, hysterectomy and bilateral salpingo-oophorectomy can be considered when medical management has failed, long-term GnRH analogue treatment is required or other gynaecological conditions indicate surgery. [GPP] Hysterectomy and bilateral salpingo-oophorectomy is a permanent form of ovulation suppression, as this removes the ovarian cycle completely; it also removes the endometrium, allowing the use of estrogen replacement without the need for progestogen. Blinded randomised studies cannot be Page 13 of 25

592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 conducted for this intervention. Observational questionnaire data suggest a highly beneficial effect in the selected women undergoing hysterectomy and bilateral salpingo-oophorectomy, the majority of whom are highly satisfied following this procedure. 102 Evidence level 2+ Severe PMS is in most cases treated successfully with medical management, but hysterectomy with bilateral salpingo-oophorectomy can be justified in women in whom medical management has proven unsuccessful, or if long-term GnRH analogue treatment would be required or if gynaecological comorbidities indicate hysterectomy. 6.5.2 Should the efficacy of this treatment always be predicted by the prior use of GnRH analogues? When treating women with PMS, surgery should not be contemplated without preoperative use of GnRH analogues as a test of cure and to ensure that HRT is tolerated. [GPP] Preoperative GnRH analogues appear to be of value in predicting the effects of oophorectomy; although such a strategy has never been tested scientifically, it would seem important, particularly when surgery is being contemplated in women of a younger age group (below 45 years) and for PMS alone. 80 Evidence level 1++ 6.5.3 What is the role of hormone replacement therapy? Women being surgically treated for PMS should be advised to use HRT, particularly if they are younger than 45 years of age. [GPP] Following hysterectomy, estrogen-only replacement can be used. The avoidance of progestogen prevents reintroduction of PMS-type adverse effects. Consideration should also be given to replacing testosterone, as the ovaries are a major production source (50%) and deficiency could result in distressing low libido (hypoactive sexual desire disorder). 103 6.5.4 Is there a role for endometrial ablation, oophorectomy or hysterectomy alone? When treating women with severe PMS, endometrial ablation and hysterectomy with conservation of the ovaries are not recommended. [GPP] Women should be counselled that oophorectomy alone (without removal of the uterus) will necessitate the use of a progestogen as part of any subsequent HRT regimen and that this carries a theoretical risk of reintroduction of PMS symptoms. [GPP] Oophorectomy is likely to be successful; however, the presence of the uterus means that combined HRT will be required and this may lead to reintroduction of PMS-like symptoms. Conservation of the ovaries will lead to persistence of PMS (ISPMD classification: PMD with absent menstruation). 104 An RCT comparing hysterectomy with the LNG-IUS in alleviating PMS symptoms as a secondary analysis showed benefit. However, the women presented with menorrhagia and diagnosis was not prospectively confirmed using a validated tool. 105 Evidence level 2 There is no reliable evidence to support endometrial ablation; however, a cohort study of 36 women with menorrhagia and PMS symptoms as rated on DRSP charts showed benefit at 4 6 months follow-up, 5.75 (P < 0.05; value = follow-up score baseline score). 106 Patients were not Page 14 of 25

642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 randomised on the basis of their PMS and prospective diagnosis was not established using validated tools. 7. Recommendations for future research Blinded RCTs comparing complementary therapies (in particular Vitex agnus-castus, vitamin B6 and calcium) with placebo. More evidence to support the use of cognitive behavioural therapy for PMS. The difficulty remains where studies cannot be blinded. Blinded RCTs comparing different regimens of drospirenone-containing oral contraceptives and long-term data regarding the risk of continuous use. Evidence to support the use of estradiol gel in the treatment of PMS. Long-term safety data regarding opposed estradiol therapy on breast and endometrial tissue within a PMS cohort. Blinded RCTs comparing tolerance to micronised progesterone versus progestogens when used as estrogenic opposition in women with PMS. Safety data for SSRIs in the early first trimester of pregnancy. 8. Auditable topics The auditable topics are based on the current ISPMD consensus and are as follows: 100% of women referred with PMS should have this diagnosis formally confirmed by completion of at least 2 consecutive months of a prospective symptom diary, usually the DRSP. 100% of women with PMS should not be offered progestogen therapy alone. 100% of women being considered for surgical treatment should have a trial of GnRH analogue therapy. 9. Useful links and support groups National Association for Premenstrual Syndrome [http://www.pms.org.uk/]: NHS Choices. Premenstrual syndrome (PMS) [http://www.nhs.uk/conditions/premenstrualsyndrome/pages/introduction.aspx]. Royal College of Obstetricians and Gynaecologists. Information for you. Managing premenstrual syndrome (PMS). London: RCOG; 2009 [https://www.rcog.org.uk/en/patients/patientleaflets/managing-premenstrual-syndrome-pms/]. References 1. Magos AL, Studd JW. The premenstrual syndrome. In: Studd J, editor. Progress in Obstetrics and Gynaecology. Vol. 4. London: Churchill Livingstone; 1984. p. 334 50. 2. O Brien PM, Bäckström T, Brown C, Dennerstein L, Endicott J, Epperson CN, et al. Towards a consensus on diagnostic criteria, measurement and trial design of the premenstrual disorders: the ISPMD Montreal consensus. Arch Womens Ment Health 2011;14:13 21. 3. Pearlstein T. Prevalence, impact on morbidity, and disease burden. In: O Brien PM, Rapkin AJ, Schmidt PJ, editors. The Premenstrual Syndromes: PMS and PMDD. Boca Raton, Florida, USA: CRC Press; 2007. p. 37 47. 4. Sadler C, Smith H, Hammond J, Bayly R, Borland S, Panay N, et al.; Southampton Women s Survey Study Group. Lifestyle factors, hormonal contraception, and premenstrual symptoms: the United Kingdom Southampton Women s Survey. J Womens Health (Larchmt) 2010;19:391 6. 5. Yonkers KA, O Brien PM, Eriksson E. Premenstrual syndrome. Lancet 2008;371:1200 10. Page 15 of 25

692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 6. Endicott J, Nee J, Harrison W. Daily Record of Severity of Problems (DRSP): reliability and validity. Arch Womens Ment Health 2006;9:41 9. 7. National Association for Premenstrual Syndrome. Menstrual Diary [http://www.pms.org.uk/support/menstrualdiary]. Accessed 2015 Aug 17. 8. Ng CY, Panay N. Management of severe pre-menstrual syndrome. In: Barter J, Hampton N, editors. The Year in Gynaecology 2002. Oxford: Clinical Publishing Services; 2002. p. 181 96. 9. Girman A, Lee R, Kligler B. An integrative medicine approach to premenstrual syndrome. Am J Obstet Gynecol 2003;188 Suppl 2:S56 65. 10. Dante G, Facchinetti F. Herbal treatments for alleviating premenstrual symptoms: a systematic review. J Psychosom Obstet Gynaecol 2011;32:42 51. 11. Whelan AM, Jurgens TM, Naylor H. Herbs, vitamins and minerals in the treatment of premenstrual syndrome: a systematic review. Can J Clin Pharmacol 2009;16:e407 29. 12. van Die MD, Burger HG, Teede HJ, Bone KM. Vitex agnus-castus extracts for female reproductive disorders: a systematic review of clinical trials. Planta Med 2013;79:562 75. 13. Prior JC, Vigna Y, Alojada N. Conditioning exercise decreases premenstrual symptoms. A prospective controlled three month trial. Eur J Appl Physiol Occup Physiol 1986;55:349 55. 14. Prior JC, Vigna Y, Sciarretta D, Alojado N, Schulzer M. Conditioning exercise decreases premenstrual symptoms: a prospective, controlled 6-month trial. Fertil Steril 1987;47:402 8. 15. Steege JF, Blumenthal JA. The effects of aerobic exercise on premenstrual symptoms in middleaged women: a preliminary study. J Psychosom Res 1993;37:127 33. 16. Stoddard JL, Dent CW, Shames L, Bernstein L. Exercise training effects on premenstrual distress and ovarian steroid hormones. Eur J Appl Physiol 2007;99:27 37. 17. Oleson T, Flocco W. Randomized controlled study of premenstrual symptoms treated with ear, hand, and foot reflexology. Obstet Gynecol 1993;82:906 11. 18. Stokes J, Mendels J. Pyridoxine and premenstrual tension. Lancet 1972;i:1177 8. 19. Abraham GE, Hargrove JT. Effect of vitamin B6 on premenstrual symptomatology in women with premenstrual tension syndromes: A double blind crossover study. Infertility 1980;3:155 65. 20. Mattes JA, Martin D. Pyridoxine in premenstrual depression. Hum Nutr Appl Nutr 1982;36:131 3. 21. Barr W. Pyridoxine supplements in the premenstrual syndrome. Practitioner 1984;228:425 7. 22. Williams MJ, Harris RI, Dean BC. Controlled trial of pyridoxine in the premenstrual syndrome. J Int Med Res 1985;13:174 9. 23. Hagen I, Nesheim BI, Tuntland T. No effect of vitamin B-6 against premenstrual tension. A controlled clinical study. Acta Obstet Gynecol Scand 1985;64:667 70. 24. Smallwood J, Ah-Kye D, Taylor I. Vitamin B6 in the treatment of pre-menstrual mastalgia. Br J Clin Pract 1986;40:532 3. 25. Kendall KE, Schnurr PP. The effects of vitamin B6 supplementation on premenstrual symptoms. Obstet Gynecol 1987;70:145 9. 26. Doll H, Brown S, Thurston A, Vessey M. Pyridoxine (vitamin B6) and the premenstrual syndrome: a randomized crossover trial. J R Coll Gen Pract 1989;39:364 8. 27. Diegoli MS, da Fonseca AM, Diegoli CA, Pinotti JA. A double-blind trial of four medications to treat severe premenstrual syndrome. Int J Gynaecol Obstet 1998;62:63 7. 28. De Souza MC, Walker AF, Robinson PA, Bolland K. A synergistic effect of a daily supplement for 1 month of 200 mg magnesium plus 50 mg vitamin B 6 for the relief of anxiety-related premenstrual symptoms: a randomized, double-blind, crossover study. J Womens Health Gend Based Med 2000;9:131 9. 29. Kashanian M, Mazinani R, Jalalmanesh S. Pyridoxine (vitamin B6) therapy for premenstrual syndrome. Int J Gynaecol Obstet 2007;96:43 4. 30. Lauritzen C, Reuter HD, Repges R, Böhnert KJ, Schmidt U. Treatment of premenstrual tension syndrome with Vitex agnus castus controlled, double-blind study versus pyridoxine. Phytomedicine 1997;4:183 9. Page 16 of 25

742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 31. Facchinetti F, Borella P, Sances G, Fioroni L, Nappi RE, Genazzani AR. Oral magnesium successfully relieves premenstrual mood changes. Obstet Gynecol 1991;78:177 81. 32. Walker AF, De Souza MC, Marakis G, Robinson PA, Morris AP, Bolland KM. Unexpected benefit of sorbitol placebo in Mg intervention study of premenstrual symptoms: implications for choice of placebo in RCTs. Med Hypotheses 2002;58:213 20. 33. Christie S, Walker AF, Hicks SM, Abeyasekera S. Flavonoid supplement improves leg health and reduces fluid retention in pre-menopausal women in a double-blind, placebo-controlled study. Phytomedicine 2004;11:11 7. 34. London RS, Bradley L, Chiamori NY. Effect of a nutritional supplement on premenstrual symptomatology in women with premenstrual syndrome: a double-blind longitudinal study. J Am Coll Nutr 1991;10:494 9. 35. Stewart A. Clinical and biochemical effects of nutritional supplementation on the premenstrual syndrome. J Reprod Med 1987;32:435 41. 36. Chakmakjian ZH, Higgins CE, Abraham GE. The effect of a nutritional supplement, Optivite for women, on premenstrual tension syndromes: II. Effect on symptomatology, using a double-blind, cross-over design. J Appl Nutr 1985;37:12 7. 37. Thys-Jacobs S, Ceccarelli S, Bierman A, Weisman H, Cohen MA, Alvir J. Calcium supplementation in premenstrual syndrome: a randomized crossover trial. J Gen Intern Med 1989;4:183 9. 38. Thys-Jacobs S, Starkey P, Bernstein D, Tian J; Premenstrual Syndrome Study Group. Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Am J Obstet Gynecol 1998;179:444 52. 39. Bryant M, Cassidy A, Hill C, Powell J, Talbot D, Dye L. Effect of consumption of soy isoflavones on behavioural, somatic and affective symptoms in women with premenstrual syndrome. Br J Nutr 2005;93:731 9. 40. Burke BE, Olson RD, Cusack BJ. Randomized, controlled trial of phytoestrogen in the prophylactic treatment of menstrual migraine. Biomed Pharmacother 2002;56:283 8. 41. Turner S, Mills S. A double-blind clinical trial on a herbal remedy for premenstrual syndrome: a case study. Complement Ther Med 1993;1:73 7. 42. Schellenberg R. Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study. BMJ 2001;322:134 7. 43. Atmaca M, Kumru S, Tezcan E. Fluoxetine versus Vitex agnus castus extract in the treatment of premenstrual dysphoric disorder. Hum Psychopharmacol 2003;18:191 5. 44. Hicks SM, Walker AF, Gallagher J, Middleton RW, Wright J. The significance of nonsignificance in randomized controlled studies: a discussion inspired by a double-blinded study on St. John s Wort (Hypericum perforatum L.) for premenstrual symptoms. J Altern Complement Med 2004;10:925 32. 45. Tamborini A, Taurelle R. [Value of standardized Ginkgo biloba extract (EGb 761) in the management of congestive symptoms of premenstrual syndrome]. Rev Fr Gynecol Obstet 1993;88:447 57. French. 46. Agha-Hosseini M, Kashani L, Aleyaseen A, Ghoreishi A, Rahmanpour H, Zarrinara AR, et al. Crocus sativus L. (saffron) in the treatment of premenstrual syndrome: a double-blind, randomised and placebo-controlled trial. BJOG 2008;115:515 9. 47. Puolakka J, Mäkäräinen L, Viinikka L, Ylikorkala O. Biochemical and clinical effects of treating the premenstrual syndrome with prostaglandin synthesis precursors. J Reprod Med 1985;30:149 53. 48. Khoo SK, Munro C, Battistutta D. Evening primrose oil and treatment of premenstrual syndrome. Med J Aust 1990;153:189 92. 49. Collins A, Cerin A, Coleman G, Landgren BM. Essential fatty acids in the treatment of premenstrual syndrome. Obstet Gynecol 1993;81:93 8. 50. Zhao J, Zhang MH, Huang W. Treatment of menstrual headache with acupuncture combined with medicine injection into acupoints. Zhongguo Zhen Jiu 1994;Supp 1:97 9. Page 17 of 25

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